Submissions for variant NM_005902.4(SMAD3):c.394A>G (p.Thr132Ala)

gnomAD frequency: 0.00003  dbSNP: rs371876622

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200310	SCV000250798	uncertain significance	not provided	2021-05-13	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 213803; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 29907982)
Invitae	RCV000541741	SCV000658881	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-19	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 213803). This missense change has been observed in individual(s) with aortic aneurysm (PMID: 29907982). This variant is present in population databases (rs371876622, gnomAD 0.004%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 132 of the SMAD3 protein (p.Thr132Ala). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt SMAD3 function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000541741	SCV001343657	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-28	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 132 of the SMAD3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with aortic aneurysm and in another two unrelated individuals affected with aortic dilation (PMID: 29907982, DOI: 10.22541/au.158739953.31329162). This variant has been identified in 5/282776 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000541741	SCV002624991	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-03-25	criteria provided, single submitter	clinical testing	The p.T132A variant (also known as c.394A>G), located in coding exon 2 of the SMAD3 gene, results from an A to G substitution at nucleotide position 394. The threonine at codon 132 is replaced by alanine, an amino acid with similar properties. This variant was reported in a thoracic aortic aneurysm and dissection (TAAD) cohort; however, clinical details were limited (Overwater E et al. Hum Mutat, 2018 09;39:1173-1192). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000845020	SCV002788432	uncertain significance	Aneurysm-osteoarthritis syndrome	2021-10-14	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV000845020	SCV000986853	not provided	Aneurysm-osteoarthritis syndrome		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 08/23/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000200310	SCV001808363	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000200310	SCV001959435	uncertain significance	not provided		no assertion criteria provided	clinical testing